This overview highlights the emergent area of mechanochemical reactions for making active pharmaceutical ingredients (APIs), and covers the latest advances in the recently established area of mechanochemical screening and synthesis of pharmaceutical solid forms, specifically polymorphs, cocrystals, salts and salt cocrystals. We also provide an overview of the most recent developments in pharmaceutical uses of mechanochemistry, including real-time reaction monitoring, techniques for polymorph control and approaches for continuous manufacture using twin screw extrusion, and more. Most importantly, we show how the overlap of previously unrelated areas of mechanochemical screening for API solid forms, organic synthesis by milling, and mechanochemical screening for molecular recognition, enables the emergence of a new research discipline in which different aspects of pharmaceutical and medicinal chemistry are addressed through mechanochemistry rather than through conventional solution-based routes. The emergence of such medicinal mechanochemistry is likely to have a strong impact on future pharmaceutical and medicinal chemistry, as it offers not only access to materials and reactivity that are sometimes difficult or even impossible to access from solution, but can also provide a general answer to the demands of the pharmaceutical industry for cleaner, safer and efficient synthetic solutions.

Mechanochemistry enables enzymatic cleavage of cellulose into glucose without bulk solvents, acids, other aggressive reagents, or substrate pre-treatment. This clean mechanoenzymatic process (coined RAging) is also directly applicable to biomass, avoids many limitations associated with the use of cellulases, and produces glucose concentrations greater than three times that obtained by conventional methods.

A simple approach is described for the identification of packing motifs in crystal structures of aromatic molecules using Hirshfeld surfaces and fingerprint plot analysis. The method was first validated by investigating previously studied molecules and establishing trends within these data, and then applied to the analysis of crystal structures of heteroaromatic molecules extracted from the Cambridge Structural Database. A series of cocrystal structures containing these same heteroaromatic molecules were also extracted and investigated using the same method. This simple method appears to be both consistent and robust in distinguishing the different types of packing motifs in structures of aromatic molecules.

Flexible metal–organic materials that exhibit stimulus-responsive switching between closed (non-porous) and open (porous) structures induced by gas molecules are of potential utility in gas storage and separation. Such behaviour is currently limited to a few dozen physisorbents that typically switch through a breathing mechanism requiring structural contortions. Here we show a clathrate (non-porous) coordination network that undergoes gas-induced switching between multiple non-porous phases through transient porosity, which involves the diffusion of guests between discrete voids through intra-network distortions. This material is synthesized as a clathrate phase with solvent-filled cavities; evacuation affords a single-crystal to single-crystal transformation to a phase with smaller cavities. At 298 K, carbon dioxide, acetylene, ethylene and ethane induce reversible switching between guest-free and gas-loaded clathrate phases. For carbon dioxide and acetylene at cryogenic temperatures, phases showing progressively higher loadings were observed and characterized using in situ X-ray diffraction, and the mechanism of diffusion was computationally elucidated.

Mechanochemistry enables enzymatic cleavage of cellulose into glucose without bulk solvents,a cids,o ther aggressive reagents,o rs ubstrate pre-treatment. This clean mechanoenzymatic process (coined RAging) is also directly applicable to biomass,avoids many limitations associated with the use of cellulases,a nd produces glucose concentrations greater than three times that obtained by conventional methods.